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Thursday, March 9, 2017

Ohio State scientist under scrutiny for accuracy

Dr. Carlo Croce is among the most prolific scientists in an emerging area of cancer research involving what is sometimes called the ''dark matter'' of the human genome. A department chairman at Ohio State University and a member of the National Academy of Sciences, Croce has parlayed his decades-long pursuit of cancer remedies into a research empire: He has received more than $86 million in federal grants as a principal investigator and, by his own count, more than 60 awards.
With that flamboyant success has come a quotient of controversy. Some scientists argue that Croce has overstated his expansive claims for the therapeutic promise of his work, and that his laboratory is focused more on churning out papers than on carefully assessing its experimental data.
But a far-less-public scientific drama has been playing out in the Biomedical Research Tower that houses Croce's sprawling laboratory on Ohio State's campus.
Over the past several years, Croce has been fending off a tide of allegations of data falsification and other scientific misconduct, according to federal and state records, whistleblower complaints and correspondence with scientific journals obtained by The New York Times.
In 2013, an anonymous critic contacted Ohio State and the federal authorities with allegations of falsified data in more than 30 of Croce's papers. Since 2014, another critic, David A. Sanders, a virologist who teaches at Purdue University in Indiana, has made claims of falsified data and plagiarism directly to scientific journals where more than 20 of Croce's papers have been published.
''It's a reckless disregard for the truth,'' Sanders said.
As a result of complaints by Sanders and others, journals have been posting notices of problems with Croce's papers at a quickening pace. From just a handful of notices before 2013 — known as corrections, retractions and editors' notices — the number has ballooned to at least 20, with at least three more on the way, according to journal editors. Many of the notices involve the improper manipulation of a humble but universal lab technique called western blotting, which measures gene function in a cell and often indicates whether an experiment has succeeded or failed.
Croce's story is a case study of the complex and often countervailing forces at work as science seeks to police itself.
Findings of fraud in biomedical research have surged in recent years, whether from an actual increase in misconduct or from heightened caution inspired in part by an internet-age phenomenon: ''digital vigilantes'' who post critiques of scientific papers on anonymous websites. Yet the primary burden for investigating and punishing misconduct falls to inherently conflicted arbiters: universities like Ohio State that stand to reap millions of dollars from the federal grants won by star researchers like Croce.
Despite the lashing criticisms of his work, Croce has never been penalized for misconduct, either by federal oversight agencies or by Ohio State, which has cleared him in at least five cases involving his work or the grant money he receives.
At Ohio State, officials said they were unaware of Sanders' charges against Croce until asked about them for this article. Now, in the wake of those and other questions from The Times, the university has decided to take a new look to determine whether it handled those cases properly.
''The university is instituting an independent external review,'' a spokesman, Christopher Davey, said in a statement, adding that the review ''is not an indication that we have discovered any evidence of scientific misconduct or other issues raised in your inquiry''.
Contacted Wednesday by The Dispatch for further comment, Davey said, in part: "The suggestion that Ohio State would tolerate research misconduct in any case, for any reason, is false.
"The New York Times implied that the university intentionally mishandled research misconduct allegations against Dr. Croce because he is a source of revenue. In fact, over the 12-year span of Dr. Croce's tenure at Ohio State, the university has invested significantly more in his research program than he has brought in from outside sources.
We take allegations of misconduct very seriously and out of an abundance of caution, in January we launched an independent review of our systems for ensuring research integrity. ... While the review is still under way, the independent experts have found to date that our policies meet national research compliance standards. They also have found no evidence that Ohio State deviated from those policies in reviewing allegations of research misconduct".
During an interview in October, and in a later statement, Croce, 72, denied any wrongdoing. He said he had been singled out in some of the accusations simply because he is a prominent figure, and he largely placed the blame for any problems with figures or text on junior researchers or collaborators at other labs.
''It is true that errors sometimes occur in the preparation of figures for publication,'' Croce said in the statement, issued through the Columbus law firm Kegler Brown Hill & Ritter. Any mistakes with figures were ''honest errors,'' he said, adding that he did not condone plagiarism but must rely on co-authors to provide proper attribution.
The new doubts about Croce's work draw carefully measured opinions from some towering figures.
Croce, chairman of the department of cancer biology and genetics at Ohio State, has since moved on to one of the hottest areas of genomics and cancer research. He has looked beyond the small fraction of human DNA that actually encodes for proteins — less than 2 percent — to the rest of the DNA, once all but ignored as contributing little to the workings of a cell.
Scientists came to realize that this DNA could make short molecules that influence how genes, and therefore living cells, operate. If genes are the notes on a keyboard, those molecules act as volume controls — regulators of gene expression.
Some of those short molecules are called microRNAs. Croce's work has linked various cancers to a deficiency or overabundance of certain microRNAs. Those effects, he asserted in a 2009 article, contribute to ''most, if not all, human malignancies.'' MicroRNAs, he posited, could lead to entirely new cancer therapies.
Once again, the scope of Croce's claims has left colleagues wary. While few researchers dispute the role of microRNA as a cancer marker, there is skepticism that the case has been made for its therapeutic potential.
''You'll find scientists who say it's hype,'' said Graham Brock, a cancer researcher who has studied the molecules. While Croce is not the only scientist who may be overselling the findings, he added, ''He's probably the strongest advocate''.
Concerns about falsified data in the scientific literature run far deeper than Croce's papers.
In a finding published in June, scientists examined more than 20,000 biomedical research papers and found that nearly 800 showed evidence of improperly manipulated images of western blots — essentially, blots obtained in one experiment that were duplicated to prove a point in an unrelated experiment. In at least half of those instances, the scientists found signs of deliberate manipulation.
The Times provided an author of that study, Elisabeth Bik, then at Stanford University, with a list of published corrections involving the blots in Croce's papers. ''Yes, the image problems in most of these are very similar to the ones we encountered,'' she said.
Because the study focused on a tiny slice of the literature that allowed researchers to see immediate problems — duplications of western blots — the potential implications are distressing, said another author, Dr. Arturo Casadevall, chairman of the department of molecular microbiology and immunology at Johns Hopkins University's School of Public Health.
''Science is built on science,'' Casadevall said. Incorrect or fraudulent papers, he said, ''could be slowing the pace of everything''.
David E. Wright, a former director of the federal integrity office, said cases of fraud could reverberate through whole fields of research.
''When you find somebody who's a leading figure in a field like that, it's kind of a pail of cold water on that part of the community,'' he said. ''It wouldn't stop colleagues from following their own research, but it's pretty discouraging. It impugns the reputation of science in general and scientists in that field in particular''.

Columbus Dispatch